Avodart® 32138

DutasterideQUALITATIVEAND QUANTITATIVECOMPOSITIONEach capsule fOi oral use contains 0.5 mg dutasteride (see List of Excipien~).PHARMACEUTICALfORMCapsules: dull yellow in colour, opaque, oblong soft gelatin capsules marked with GXCEl.CLINICALPARTICULARSIndicationsAVODART treats and prevents progression of benign prostatic hyperplasia (BPH) through alleviatingsymptoms. reducing prostate size (volume), improving urinary flow rate and reducing the risk of acuteurinary retention (AUR)and the need for BPH·related surgeI)'.In addition, AVODART in comblnation with the alphs-blocker tamsulosin, treats and prevents progressionof benign prostatic hyperplasia (BPH) by reducing prostate size, alleviating symptoms, improving unnal)'flow and reducing therisk of acute urinal)' retention (AUR)and the need for BPH·related surgeI)' (seeOinical Studies).Dosage and AdministrationAdult males (induding elderly)Capsules should be swallowed whole and not chewed or opened, as contact with the capsule contentsmay result in irritation of the oropharyngeal mucosa.AVODART may be taken with or without food.The recommended dose of AVODART is one capsule (0.5 mg) taken orally once a day.Although an improvement may be observed at an early stage, treatment for at least 6 months may benecessary in order to assess objectively whether a satisfactory response to the treatment can be achieved.For treatment of BPH,AVODART can be administered alone or in combination with the alpha·blockertamsuJosin (0.4mg).Renal impairmentThe effect of renal Impairment 00 dutastende pharmacokJnetics has not been studied. However, no$!ment in dosage is anticipated for patients with renal Impainnent (see Pharmacokinetics).Hepatic impairmentThe effect of hepatic impalfTllent 00 dutas,ende phannacoldnetics has not been studied ~ee Warningsand l'Tecautioos and PharmacokJneool.ContraindicationsAVODART is cootraindicated in panents WIth known hYPffi'nsitivity to dutasteride, other5 -alpba-reductase inhibitors. or any component of the preparation (see Ust of Excipien~).AVODART is contraindicated for use in women and children (see Pregnancy and Lactationl..Warnings and PrecautionsDutasteride is absorbed through the skin, therefore women and children must avoid contact with leakingcapsules (see Pregnancy and Lactation). If contact is made with lea,ing capsules the contact area shouldbe washed immediately with soap and water.The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Becausedutasteride is extensively metabolized and has a half·life of 3 to 5 weeks. caution should be used in theadministration of dutasteride to patients with liver disease (see Oo"'ge and ADministration andPharmacokinetics).Combination Therapy with Tamsulosin and cardiac failureIn two 4-year clinical studies, the incidence of cardiac failure (a composite tenn of reported events.primarily cardiac failure and congestive cardiac failure) was higher among subjects taking thecombination of AVODART and an alpha blocker, pnmanly tamsulosin, than it was among subjects nottaking the combination.Inthese two trials, the incidence of cardiac failure was low (~1%) and variablebetween the studies. No imbalance was observed in the incidence of cardiovascular adverse events overallin either trial. No causal relationship between AVODART (alone or in combination with an alpha blocker)and cardiac failure has been established (see Clinical Studies).Effects on prostate specific antigen (PSA) and prostate cancer detectionDigital rectal examination, as well as other evaluations for prostate cancer, should be performed onpatients prior to initiating therapy with dutasteride and periodically thereafter.Serum prostate-specific antigen (PSA) concentration is an important component of the screening processto detect prostate cancer.AVODART causes a decrease in mean serum PSA levels by approximately 50% after 6 months oftreatment.Patients receiving AVODART should have a new PSAbaseline esta~ished after 6 months of treatmentwith AVODART. It is recommended to monitor PSA values regularly thereafter. Any confirmed increasefrom lowest PSAlevel while on A VODART may signal the presence of prostate cancer (particularly highgrade cancer) or noo-conpliance to therapy with AVODART and should be carefully evaluated, even ifthose values are still within the normal range for men not taking a Sa-reductase inhibitor (see ClinicalStudies). In the interpretation of a PSAvalue for a patient taking AVODART, previous PSAvalues shouldbe sought for comparison.Treatment with AVODART does not interfere with the use of PSA as a tool to assist in the diagnosis ofprostate cancer after a new baseline has been established.Total serum PSA levels return to baseline within 6 months of discontinuing treatment.The ratio of free to total PSA remains constant even under the influence of AVODART. If clinicians elect touse percent-free PSA as an aid in the detection of prostate cancer in men undergoing dutasteride therapy,no adjustment to its value is necessary.Prostate cancer andJli~~ltllllllll~-==---""",--, __ ",,In a 4-year study of over 8,000 men aged 50 to 75, with a prior negative bTopsYfDr prostate cancer andbaseline PSAbetween 2.5 nglmL and 10.0 nglmL(the REDUCEstudy), 1,517 men were diagnosed withprostate cancer. There was a higher incidence of Gleason 8-10 prostate cancers in the AVODART group(n=29, 0.9%) compared to the placebo group (n=19, 0.6%). There was no increased incidence in Gleason5·6 or 7·10 prostate cancers. No causal relationship between AVODART and high grade prostate cancerhas been established. The clinical significance of the numerical imbalance is unknown. Men takingAVODART should be regularly evaluated for prostate cancer risk induding PSA testing (see ClinicalStudies).InteractionsIn vitro drug metabolism studies show that dutasteride is metabolised by human cytochrome P450isoenzyme CYP3A4. Therefore blood concentrations of dutasteride may increase in the presence ofinhthitcrs of CYP3A4.Phase 1I data showed a decrease in clearance of dutasteride when co-administered with the CYP3A4inhibitoo verapamil (37%) and diltiazem (44%). In contrast no decrease in clearance was seen whenamlodipine. another calcium channel antaqonst, was co-administered with dutasteride. A decrease indearance and subsequent increase in exposure to dutasteride, in the presence of CYP3A4 inhibitOf\ isunlikely to be dinically significant due to the wide margin of safety (up to la-times the recommendeddose has been given to patients for up to six months), therefore no dose adjustment is necessary.In vitro, dutastende is not metabolized by human cytochrome P450 isoenzymes CYP1A2,CYP2C9,CYP2C19, and CYP2D6.Dutasteride neither inhibits human cytochrome P4S0 drug-metabolizing enzymes in vitro nor inducescytochrome P 450 isoenzymes CYP1A.CYP2B,and CYP3A in rats and dogs in vivo.In vitro studies demonstrate that dutasteride does not displace warfarin, diazepam, or phenytoin fromplasma protein, nor do these model compounds displace dutasteride. Compound. that have been testedfor drug interactions in man include tamsulosin, terazosin, warfarin, digoxin, and cholestyramine, and noclinically significant interactions have been observed.Although specific interaction studies were not performed with other compounds, approximately 90% ofthe subjects in large Phase III studies receiving dutasteride were taking other medications concomitantly.No clinically significant adverse interactions were observed in clinical trials when dutasteride wasco-administered with anti-hyperlipidemks, angiotensin-converting enzyme (ACE) inhibitors.beta-adrenergic blocking agents, calcium channel blockers. corticosteroids, diuretics, OOf1Steroidalanti-inflammatory drugs (NSAIDs),phosphodiesterase Type V inhibitors, and quinolooe ..,tibiotics.A drug interaction study with tamsulosin or terazosin administered in combination WI AVODART fortwo weeks showed no evidence of pharmacokinetic or pharmacodynamic interactions.Pregnancy and lactationfertilityelf

18 to 52 (n:27 dutastende, n:i3 placebo) tIvoughoot 52 woeI:s of treaunent and 24 woeI:s of pos1treatment follow-up. At 52 weoks. the mean percent redu<tJon from baler"", II \Dtal sperm Cvolume. and sperm ITlOlllitywere 23'1', 26'1., and 18%, respecIJveiy, m the dutastende groupadjusted for changes hom baseline In the placebo group. Sperm concentraoon and sperm rnorpiIoiogJ..,re unaffected.Aher 24 weeks of follow·up. the mean percent change In \Dtal sperm count IIIdutastende group remained 23% lower than baseline. While mean values for all semen paramelf<S.r.ume POints remained within the normal ranges and did not meet p<ecleflned onena for a dime.~gn1ficant change (30%), two sublects m the dutasteride group had decreases In sperm count of geaterthan 90% horn baseline at 52 weeks, with partial recovery at the 24·week foIlow·up. The clinicalsignificance of dutasteride's effect 00 semen characlerislKs for an individual patient's fertility" notknown.Pregnancy .o..:;!.t.ridOi'(Qntraindic:.r.edlforuselbyw,,",,~Dutast . women ausepre-clII1KaIdata suggests that the suppresSioo of ",culanng levels 01 dihydrotestosterone may Inhibit thedevelopment of the external genital organs In a male foetus carried by a wornan exposed to dutastende.lactation~ " not kOOMlwhether dutasteride "excreted In breast milk.Effects 00 Ability to Drive and Use Machines8ased 00 the pharrnac:'*ineuc and pharmac:odynaffiICp<operties of dutasteride trea_ Withdutastende would not be expected to inte"ere with the ability to drive or operate machrnery.Adverse reactionsClinical trial dataAVOllART Moootherapy for BPHThe folluwing investigator·judged drug-related adverse events (with inodence ~1'11r1have been..portedPlOrecornmoniy in tlYee phase IIIplacebo cootrolled studies 00 AI'OOART treaunentcompared to:<OC!IiI> -

1 •••••~M!t: Ir<ido<u M"9 leal 1 of treatment In<idenc:e during year 2 of treatmentPlacebo AI'OOART Placebo AVOOARTtn: 2158) (n: 2167) tn: 1736) (n-17441

lmootence 3% 6% 1% 2%Altered (decreased) 2% 4% <1% <1%libido8aculation disorders <1% 2% <1% <1%Breast disor~+ <1% 1% <1% 1%+ includes breast tenderness and breast enlargementNo change to the adverse event p<ofilewas apparent..., a further 2 years •• operHabeI ext""lOIl '.studres. - _.AVOOART and Tarnsulnsin Combination Therapy for BPH ~.The followrng investrgator·judged drug·relaled adverse events (with a cumulative incidence of greaterthan or equal to 1%) have been reported in the CombAT (Combtnaoon of AI'OOART and Tamsulosln)S ,. a companson of AI'OOARTO.5mg and tamsulesm 0.4mg once daily for four years ~ cornbrnation••.&~

A<Iftrv acnon Incidence during treatment periedYear 1 Year 2 Year 3 Year 4

CombinatiOO'(n) (n:1610) (n:142B) (n:1283) (n:1200)Outasteflde ~~~:~~~l(n:1464) ~~~:~~~l~~~:~~lTamsulosin in:1468i

ImpotenceCombination- 6% 2% <1% <1%Dutasteride 5% 2% <1% <1% IITamsulosin 3% 1% <1% 1%

Altered (decreased) libido IICombinatiOO' 5% <1% <1% 0%Outasteride 4% 1% <1% 0%Tarnsu1o~n 2'lIo <1% <1% <1%

Ejaculation disordersCombinatiOO' 9% 1 <1% <1%Outasteride 1% <1% <1 ••• <1%Tamsulosin 3% <1% <1% <1%

Breast disorders'(ombinatio,yl 2% <1% <1% <1%= 2% 1% <1% <1%

<1% <1% <1% 0%

~ I-.-. I <1'110 <1% <1%,.......,.. ~~.<1% <1% <1% II<1'110 <1% 0%,~:

:nas:~-0.4 mg once daily.

dN~ drug ",actIOnS are hsted below by system organ class and frequency. Frequenaes are defined as:ve<y(ommon (21110), common (211100 to <1110), tJ1l(ommon (21Moo to <11100), rare (21110,000 to<111000) and ve<y rare «1110,000) Including isolated reports. Frequency categories (Jetermined frompost-mari<eting data refer to repor1lng rate rather than true hequency.Immune system disordersVery rare: AJlergk reactiorls. including rasll. pl'URllIs, urticana, Iocalrsed oedema. and angioedema.Skin and subcutaneous tissue disordersRare: Alopeoa (primarily body hair kos), HypertrichosISOverdoseIn volunteer studies single doses of dutasteride up \D40 m~ (SO_ the therapeutK dose) for7 days have been administered without ~jfieanl safety concerns. IIIcinKaI studies doses of 5 mg dailyhave been administered to patients for 6 months with no additional adverse effects to those seen attherapeutic doses of 0.5 mg.There is no spedfic antidote for dutasteride therefor~ In cases of suspected overdosag~ symptomatIC andsupportrve treatment should be glVerlas app'opriate.PHARMACOLOGICALPROPERTIESPharmacodynamicsOutasteride is a dual inhibitor of 5 alpha·reductase. It inhibits both type 1 and type 2, 5 alpha-reductasencienzymes. which are responsible for the conversioo of testosterone to dihydrotestosterone (OHn. OHTisthe androgen primarily responsible for hyperplasia of glandular prostatic tissue.Effects on DHTrrestosteroneThe maximum effect of daily doses of AVOllART 00 the redoction on OHTis dose-dependent and isobserved within lto 2 weeks.Aher 1 week and 2 ~of daily doslngofAVOllARTO 5 mg. medianserum DHTconcentrations were reduced by 85% and 90%, respec1rveIy.In BPHpatients treated with 0.5 mg of dutasteride daily, the median decrease in OHTwas 94'1irat 1 yoarand 93% at 2 yoa~ and the median increase in sen.m testosterone was 19% at both 1 and 2 years. ThISisan expected consequence of 5 alpha-reductase inhibition and aK! not resLlt In any known adverse evenPf1armacoieineticsAbsOfPtionDutastende is admlnrstered orally In solution as a soft gelaun capsule. follOWIngadminIStration of a ~ngle0.5 mg dose, peak serum concenttatlons of dutasleride occur within 1 to 3 hours.Absolute bioavailability In man is approximately 60% relative to a 2 hour intravenous infusion. Thebioavailability of dutasteride is not affected by food.DistributionPharmacokinetic data follOWingsingle and repeat or~ doses show that dutasteride has a large volume ofdlStnbutloo (300 to 500 l). Outasteride is highly bound to plasma protans (>99.5%).following daily dosing. dutasterrde serum concentratIOnS achieve 65% of steady state (oncenttatlOn afterI month and app<oximately 90% after 3 months. Steady state serum concentratIOnS (Css) of

approXimately 40 nanograms/ml ••• achieved after6 months of dosing 0.5 mg once a day. Similarly to serum, III Idutasteride concentrations semen achieved steady stateat 6 mooth, After 51 weei<s 0 therapy, semen dutasterideconcentr.tIons _aged 3 4 """"'Jfams/ml (range 0.4 to14 nanograms/ml). Outasteride partitioning from seruminto semen averaged 11.5%.BiotransformationIn WlTO, dutasteride is metabolized by the humancytochrome P450 isoenzyme CYP3A4to two minormonohydroxylated metabolites. but it is not metabolizedby CYPIA1, CYP1C9,CYP1C19 or CYP106.In human serum, following ""ing to steady state tIlChanged dutastende. 3 INfO' metabol tes(4'-hydroxyt!utasteride, l,l.iJhydrcd.1aS:e<<ie ~ 1'*-"""" l' ~- :is

(6,4'-dihydroxydutasteride andf~S4~-~.:~:~~"'~II<::""~;":-·~~~=~~~:;~~-been detected. The five humanhowever the stereochemIStry of tr<!metabolites ts not known.EliminationDutastende is extensively metabol1l'!Lhumans, 1~ to 15.4% (me,.. of 5 • "" OOX 5 • asThe rem. nder ISexcreted in the faeces as map rretatlO' tes anpns "'l 39'00 I'of drug-related material and 6 nunor metabohtes Oess than 5'" each).Only trace amounts of unch.nged dutastende (less than 0.1% of the dose) are detected in human urine.At therapeutic concentrations, the tenminal half-life of dutasteride is 3 to 5 weeks.Serum concentratioos rem.in detectable (greater than 0 1 nglmU f(l( up to 4 to 6 months afterdiscoo -nuation of treatmentlinearity/non-linearityDutastende pharmacolullelKS can be described as rrm (l(de< """'"eI minatioo path~ one saturable (concentr~arantr.tion-Independen"• serum concentratrons (less than 3 na~.'!:l!1I, Qltas;;""""conc!fltratioo-dependent and concentra~.less showed evidence of rapid clearance and. s/lor: . 1•• 3 9 daIS-At serum concentranons. greater than 3 n.nogramsllnl.dutastinders_slowIj 35 ••056pnmarily by Ilneat oon-saturable elimrnatioo WIthtemuna half·1fe of 3 to 5 wee<s. Atconcentrations, fol\pw1ng repeat dosing of 0.5 mglday, the slower clearance dominates and the totaldesrance is linear and concentratton-independent.ElderlyDutasteride pharmacokinetics and pharmacodynamics were evaluated in 36 healthy male subjectsbetween the ages of 14 and 87 years following acminsnation of a single 5 mg dose of dutasteride.Exposure of OOtasteride, represented by AJJCand Cmax values. was not statistical~ differenl whenc","paring age group' Haff·lifewas not sta 'stical~ different when c","paring the 50-69 year old groupto the gre.ter than 70 years old grou~ whreh encompasses the age of most men with 8PH. No differencesin drug effect as measured by DHTreduction were observed between age groups. Resul~ indicated thatno dutasteride do<e-adjustment based on age is necessary.Renal impairmentTheeffect 0' renal impalnment 00 dutasteride p/rarmacoi<lnetJci has not been studiM. However. less than0.1% of a steacly·st.te 0.5 mg do<e of dutastende • rec"",red In hum"" Uf1Ile. so no adjustmfl1t Indosage is anticipated for pattents with renal impairmentHepatic impairmentThe effect 00 the pham\acokinetics of dutasteride in hepatic impairment has not been studied ~••Vl.!mmgs and PrecautJonsl.Ginkal studiesAVODART monotherapy for BPHDutasteride 0.5 mglday or placebo was evaluated in 4315 male subjects with enlarged prostates (greaterthan 30 ee) in three primary efficacyl·year multicenter, placebo-controlled, double-blind studies.

men with BPH,AIOOART trea~ and prevents disease progressioo by reducing the risk of both acute"""ry retentioo (A .nd the need f(l( surgical Intervenlion (5Qand by providing statistically significant"'!'fO'IOment of lower ",nary tract sympt"'"s (lUTI), maximum urinary flow rate (Omax) and prostate,",ume relative to placebo. These improvements in lUT5, Omax end prostate volume were seen throughto 14 months, and lUTI and Omax cootinued to ,m(l(oved for a further 1 vears IIIO\lerI.JabeIextensron

. Inaddmon.~ f ~l - -- --s-,:x:s:•• tenS stud>es.AVODART and tamsulosin c BPHAVODARTOSnglday, tamsu!oso - combrna 00 of AVODARTO.5mg plus tamsulosin0.4mg was evaluated in 4844 ma~ enlarged prostates (greatel than or equal to lOee) in amulticentec double blind. parall~ _1 years. The primary efficacy endpoint at 1 years oftre.tment was the level of im""",," b.JseI;ne m the Intematiooal prostate symptom score (IPSS).After 1 years of treatment. com~ showed a statistically Significant adjusted meanmprovemet1 In symptom scores basi- ::If of -6.2 units. The adjusted mean improvements insymptom SCll(esobserved with the IndMdua therapies were ·4.9 uruts for AVOOART and 4.3 uni~ fortamsulosin. The adjusted mean rmprovemeo in flow rate from baseline was 2.4 ml/sec for thecomblnaton, 1.9 mVsec for AVODART.nd 0.9 mUsec for tamsu!osin. The ad' led mean im ravement inBPHlrnpadlndex(B""," newas-l.1 unitsf(l(thecombinatioo.·l AVOO4RTand-'.5 (I(tafllSlJ!OSin.

The reduction intotal;~~~~~§~~~~~~§~~~~~r.~statis"",IIy significant... BOO

The prtmary efficacy ~ at ~ yearssurgery. After 4 ye'" 0'!rEa t.(I( BPH·related surger, 65 &' reductioo II" 95,".: >' j~,,,tamsu!osin moootherapy. The ncidence of ,or Bi'"_ '?""Icombmation therapy and 11.9% for tamsu!osin (IKO.OOIJ.Conpared to Acombination therapy reduced the risk of AJJRor BPH-related surgery by 19.6"; the d' I!!ence belY«<'fltreatment groups was not significant (p=0.18 [95% (1-10.1)% to 41.7%[). The incidence of AJJRor8PH·relatedsurgel)'1rfYear4was4.1%fQf~~5.1 forAVODARr.Chnreal progression was defined as a composite of worsenmg symp IPSII, and BPH-related even~of AUR,incootJnence, UTI,and renal <Jency. C was assoaaled With. sta stKallysignificantilylower rate of clrnrcal fJfOC1e\S'OOCIlIIICWed 001 44 1" ns.\ reOOalorr[95 % CI:33.6'" to 53.0"'}1 after 4 years. fa

tamsuklSll,andAVODART lL~E2~15~~ancE~§;~~E~=~The stansnca significant act.&l!!1maintained from year 1 to year 4 ! years.observed were -6.3 units for comb",.- :!1erapy -5 3 ""tamsulosin monotherapy.After 4 years of treatment, the -sEd 111M' .~. "!:;:,\~~,~:::~e;:1.4 mUsec forcombinatioo therapy, 1.0 /see foeA.oo.:..'· .moootherapy. Compared with tamsulosin, the adjusted mean ImJl'O'l!!11l!!lfrom basel lie Qrnax wasstatistically significantly greater WIthcombination therapy at each 6·month assessment from Month 6 toMonth 48 (p<O.OOl).Compared with AVODART, the adjusted mean improvement from baseline in Omaxwas not statistically SlCjnrficandydifferent than with combination therapy (p=0.050 at Month 48).Comblnatioo therapy was sign,ficantly superior (p<O.OOI) to tamsu!osln monotherapy and to AVODARTmoootherapy f(l( the rmprovoment in healttl outcome parameters BIIand BPH-rel.ted Healttl5t.tus (BHS)at 4 years. The adjusted me,.. ,mprovement in BIIfrom baseline was ·1.1 units for the combinanon·l.B for AVODART and -1.1 for tamsulosin. The adjusted mean improvement in BHSfrom basehne was-1.5 units for the comb,natioo, -1.3 for AVODART and -1.1 for tamsuiosin,The reduction in total prostate volume and transition zone volume after 4 years of treatment wasstanstically significant foe combinatioo therapy compared to tamsulosin moootherapy alone.Cardiac failureIn a 4·year comparison of AVODART coadministered with tamsulosin and dutasteride or tamsulosin .monothera in men with BPH(the CombATstud I,the incidence of the com Site term cardiac farlure In

the combination group (14/1610, 0.9%) was higher than in eittier monoTherapYWOiiji'7WOlYA/lf.47\ b23(0.2%) and tamsulosin, 10/1611, (0.6%). The relative risk estimate for time to first cardiac failure eventwas 3.57 [95% Cll.17, 10.8[ forcombination treatment compared to AVODART monotherapy and 1.36[95% CI 0.61, 3.07[ compared to tamsulosin monotherapy. No causal relationship between AVODART(alone or in combination with an alpha blocker) and cardiac failure has been established (see Warningsand Pr"aulions).In a 4-yearcomparison of placebo andAVODARTm 8231 men aged 50 to 75, with a prior negative biopsyfor prostate cancer and baseline PSAbetween 2.5 nglmL and 10.0 nglmL (the REDUCEstudy) there was ahigher incidence of the composite term cardiac failure in subjects taking AVODART (30/41 05, 0.7%)versus placebo (16/4126, 0.4%) for a relative risk estimate for time to first cardiac failure event of 1.91[95% Cll.04, 3.50[. In a post-hoc analysis of concomitant alpha blocker use, there was a higher incidenceof the composite term cardiac failure in subjects taking AVODART and an alpha blocker concomitantly(12/1152,1.0%), compared to subjects not taking AVODART and an alpha blockerconcOmitan .AVODART and no a!pha blocker (18/2953, 0.6%), placebo and an alpha blocker (111399, <0.1 %), placeboand no alpha blocker 1512727, 0.6%). No causal relationship between AVODART (alone or in combinationwith an alpha ~ocker) and cardiac failure has been established (s", Warnings and Precaunons).Prostate cancer and high grade tumoursIn a 4-year companson of placebo and AVODART in 8231 men aged 50 to 75, with a prior negative biopsyfor prostate cancer and baseline PSAbetween 2.5 nglmL and 10.0 nglmL (the REDUCEstudy), 6,706subjects had prostate needle biopsy data available for ~nalysis to determine Gleason Scores. There were1517 subiects diagnosed with prostate cancer in the study. The majority of biopsv-detectable prostatecancers in both treatmef1t groups were diagnosed as low grade (Gleason 5-6). There was no difference inthe incidence of Gleason 7-10 cancers (p=0.81).There was a higher Incidence of Gleason 8-10 prostate cancers in the AVODART group (n=29, 0.9%)compared to the placebo group (n=19, 0.6%) (p=0.15).ln Years 1-2, the number of subjects with Gleason8-10 cancers was sim·.a<in AWllMR groop 11=17,0.5 andtheplacebo 11=18,0.5Years l-4. more G~ason 8-10 cancers were diagnosed in the AVODART group (n= 12, 0.5%) comparedwith the placebo group (n= I,&1%) (p=0.OO35).There are no data available on the effect of AVODARTbeyond 4 )'I'ar, n men at risk of prostate cancer. The percentage of subjects diagnosed wilh Gleason8-10 car""" was consistent across study time periods (Years 1-2 and Years 3-4) in lhe AVODART group(0.5% in ,ach me period), while in the placebo group, the percentage of subj"ts diagnosed withGleason 8-10 Glncers was lower during Years 3-4 than in Years 1-2 «0.1 % versus 0.5%, respectively). Ina 4 year BP study (CombAn where ther, were no protocol-mandated biopsies and all diagnoses ofprostate GII"Uf were based on for-cause Mpsles, the rates of Gleason B-l0 cancer were (n=B, 0.5%) forAVODART, rn= II, 0.7%) for tamsulosin and (11=5,0.3%) for combination therapy (see Warnings andPrecautionsEffects on prostate specific antigen (PSA) and prostate cancer detectionIn a 4-yearcomparison of placebo and dut.1stende in 8231 aged 50 10 75 a ••••. _~ •••• , ~ __ Ibiopsy for prostate cancerand baseline PSAbetween 2.5 "!t:1- and 10. '9""- ll1I'RfiJUCEAVODART treatment caused a decrease in mean serum PSA I1j approxunately 5O'ioa er six months oftreatment with a Jarge variability (standard deviation of 31)'!" among patrents. The PSAsuppressionobserved at six mooths was similar in men who did or who dKt not develop biopsy-detectable prostatecancer during the study. (see Warnings and Precautions).Incidence of breast cancerIn BPHmonotherapy clinical trials, providing 3374 patient years of exposure to AVODART, there were2 cases of breast cancer reported in AVODART -treated patients. one after 10 weeks and one after11 months of treatment and 1 case in a patient who received placebo. In subsequent dinkal trials in BPHand B231 men aged 10 to 71, with a prior negative biopsy for prostate cancer and baseline PSAbetween25 nglmL and 10.0 nglmL providing 17489 patient years exposure to AVODART and 5027 patient yearsexposure to AVODART and tamsulosin combination there were no additional cases in any of the treatmentgroups. The relationship between long term use of dutasteride and male breast cancer is unknown.Pre-clinical safety dataAt exposures gready in excess of those a' the clinical dcse. ~ rtllfKIlI!(Iiic CNS-re!a:ed effectswere seen in rats (421-fold) and dogs 'lIS-tooOther toxicity findings were COOSr<tfnt pi'<rma<lliogKaI actIV!t, of 5 aIp/la-feduct2s ilOll

In male rats and dogs. these included e"ects on aro5Sllf'/ reproduc!Ne organs aOO.l1m<~ ..". areversible decrease in fertility. This is cOl'lSideted to hav-e 00 d'n.ca re.eva'lCe as e ~ no ~ 00

sperm development, concentratJOll '" molrty. ffm msatJOll 0 the extemaI ge"".!ia was noted in malefoetuses of female rats and rabbits ",ally dosed with dutastetide. However, rntr.lYeOOUSadmrnlStration ofdutasteride to pregnant Rhesus monkeys dunng embryofoetal development at doses of up to2010 nanogram lanimal/day did not produce adv"" matennal or foet.11toxkity. This diose represents amultiple of at least 186-fold (nanogram I1<gbasis) the potential maximum daily dose in a 50 kg woman,resulting from exposure to 5 ml semen (assuming too% absorption) from a dutasteride-treated man.Dutasteride was not genotoxic in a wide range of mutagenicity tests.In carcinogenicity study in rats. there was an increase in benign interstitial cell tumours in the test is at thehigh dose (15B-fold clinical exposure). However. the endocrine mechanisms believed to be involved in theproduction of interstitial cell hyperplasia and adenomas in the rat are not relevant to humans. There wereno dinically relevant effects on tumour profile in a carcinogeOldty study in mICe.PHARMACEUTICALPARTICULARStlst of ExcipientsCapsule contents: monodiglycerides of caprylidcapric add; lxrtyIated hydroxytolueoeCapsule shell: gelatin; glycerol; titanium dioxide (E171, CI 77891); iron o~de )'I'flow (E172, CI 77492);Medium chain triglyt:erides and lecithin as capsule lubricants.Special Precautions for StorageDo not store above 30°C.Nature and Contents-of ContainerPVClPVDCblistersInstructions for Use/HandlingDutasteride is absorbed through the skin, therefore women and children must avoid contact with leakingcapsules (see Warnings and Precautions and Pregnancy and t.actarion).lf contact is made with leakingcapsules the contact area should be washed immediately with soap and water.

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INSTRUCTIONSTO THE PATIENTTHISISAMEDICAMENT

Medicament is a product which affects your health, and its consumption contrary to instructions isdangerous fOfyou.Follow strictly the doctor's prescription, the method of use and the instructions of the pharmacistwho sold the medicament.The doctor and the pharmacist are experts in medicine, its benefits and risks.Do not by yourself, interrupt the period of treatment prescribed for you.Do not repeat the same prescription without consulting your doctor.

KEEPMEDICAMENTOUTOf REACHOf CHILDRENCouncil of Arab Health Ministers

Union of Arab PharmacistsManufactured by: Catalent France Beinheim SA Bernheim, FrancePacked by: Glaxo Saudi Arabia Ltd.', Jeddah - KSA"member of the GlaxoSmithKline group of companies

Version number: GDS15/1PI1lDate of issue: 24 MARCH 2011

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